Study on the Synthesis, Structure and Antimicrobial activity of the new Mannich base and its Transition Metal Complexes Derived from Phthalimide

 

A. Balakrishnan¹, Dr. A. Sankar²*

¹Assistant Professor, PG and Research Department of Chemistry, Govt Arts College, Dharmapuri, Tamilnadu, India

²Assistant Professor, PG and Research Department of Chemistry, Kandaswami Kandars College, P. Velur, Tamilnadu, India

 

ABSTRACT:

Cyclic aromatic secondary amines, like phthalimides, and related compounds possess structural features, which makes them to exert potential biological activities and pharmaceutical applications. A new Mannich base has been synthesized from phthalimide and its transition metal complexes also were prepared. The Mannich base ligand was synthesized by using phthalimide, formaldehyde and piperidine. The ligand as well as the metal complexes were characterized by various physical methods. The structure of the synthesized compounds are confirmed by UV, IR, and ¹H NMR spectroscopic techniques. The antimicrobial activity of the ligand and the complexes were examined using different bacteria by disc diffusion technique.

 

 

 

1. INTRODUCTION:

Nowadays, toxicity and resistance play an important role in drug development for the treatment of diseases due to microbes, helminthes and insects. Thus there is still a search for new antimicrobial, anthelmintic and insecticidal agents. N-Mannich bases derived from phthalimide analogous have been extensively used in medicinal chemistry owing to their wide range of biological applications reported in literature. Phthalimide is a colorless solid aromatic imide in which two carbonyl groups bound to an amine functional moiety. It is a very important starting synthone for organic synthetic chemists to prepare diverse biologically active molecules.

Numbers of phthalimide derivatives have been synthesized incorporated with interesting biological activities^1-3 and liquid phase crystalline properties⁴, as well as find varied applications in industrial field.

 

 

Phthalimide and its derivatives have received much attention due to its versatile biological and pharmaceutical activities such as antimicrobial^5,6, antihypertensive^7,8, anti-viral⁹, antitumor¹⁰, anti-inflammatory agents^11,12, as a inhibitors of HIV-I integrase¹³and serve as ligands to form bioactive metal complexes. Heterocyclics is the key structure in numerous natural and synthetic compounds having therapeutic importance^14-16. The above mentioned literature and privileged structure made us to synthesise some novel molecules by taking phthalimide and heterocyclic amine as a bioactive key phamacophore. In the present study we have synthesized a new N-Mannich base of the phthalimide and three transition metal complexes. The ligand and the complexes were characterized by spectral data and evaluated for their antimicrobial activities.

 

2. MATERIALS AND METHODS:

2.1 General:

All the reagents used for synthesis of the ligand and the metal complexes were of A.R. grade. The solvents used were commercial products of the available purity and were further purified by distillation. IR spectra were recorded using Perkin Elmer FT-IR spectrometer by using KBr pellets. Absorbance in UV-Visible region was recorded in DMF solution using UV-Visible spectrometer. The ¹H NMR of the ligand was recorded on a Bruker instrument employing TMS as internal reference and DMSO-d6 as solvent.

 

2.2 Synthesis of the ligand Piperidino Methyl Phthalimide (PMP):

0.05 mol of Phthalimide, and 0.05 mol of Formaldehyde are dissolved in 100 mL of ethanol and taken in a 250mL RB flask. Then 0.05 mol of the Piperidine dissolved in 50 mL ethanol added in small aliquots to the reaction mixture kept in ice bath and the stirring was continued for about 3hrs. Then it is cooled in refrigerator for overnight. After cooling it for a night, the contents are refluxed for about 5 hrs, again kept in refrigerator. Next day, the solvent was recovered from the mixture by distillation. Mannich base separates out as colourless solid. It is filtered and washed with hot water, recrystallised in alcohol and dried in air-oven at 60°C.The yield is found out to be about 76%.

 

 

Fig.1 . Reaction Scheme for the synthesis of the ligand

2.3 Synthesis of Metal complexes:

0.01 mol of the ligand is dissolved in 10mL of ethanol taken in a 50mL RB flask and with this 0.01 mol of the metal chloride dissolved in 10mL of distilled water was added. Then the contents of the flask were refluxed for about 3 hrs. A characteristic coloured precipitate settles at the bottom. It was filtered, dried in air oven at 60˚C and recrystallised from alcohol.

 

Table 1 : Physical data of the ligand and the complexes

Compund	Yield (%)	Colour	Mp (°C)
PMP -Ligand	70	Colorless	242
PMP -Co	75	Pale pink	213
PMP-Ni	78	Pale green	235
PMP -Cu	76	Pale blue	248

 

2.4 Antibacterial activity:

For the antibacterial study, nutrient agar was used as the medium. The ligand as well as the complexes were screened for antibacterial activity against certain pathogenic bacteria by disc diffusion method at concentration of 10µg / ml in DMSO using Bascillus subtilis, Staphaylococcus aureus, Escherichia coli and Pseudomonas aeruginosaa. The paper disc containing the compound (10, 20 and 30 μg/disc) was placed on the surface of the nutrient agar plate previously spread with 0.1 mL of sterilized culture of microorganism. After incubating this at 37^oC for 24 hrs, the diameter of inhibition zone around the paper disc was measured.

 

The zone of inhibition was measured in mm and the activity was compared with Gentamycin in 1 µg / disc A comparison of the diameters of inhibition zones of the compounds investigated shows that Cu(II) complex exhibit highest antibacterial activity against all the bacterial species studied. The results are tabulated in Table.2.

 

 

 

 

 

 

 

 

 

Table 2: Antibacterial activity

Samples	Escherichia coli (mm)	Staphylococcus aureus (mm)	Bacillus subtilis (mm)	Pseudomonas aeruginosa (mm)
Ligand (50μl)	1.60±0.09	1.90±0.06	0.90±0.07	1.30±0.07
Co Complex (50μl)	2.70±0.17	1.80±0.11	1.40±0.07	2.50±0.07
Ni Complex (50μl)	1.80±0.05	0.50±0.01	0.70±0.01	0.40±0.02
Cu Complex (50μl)	5.40±0.40	5.10±0.37	3.20±0.23	4.20±0.28
Standard (30µl)	9.40±0.65	8.80±0.61	8.40±0.58	8.70±0.60
Control (Solvent) (30µl)	0	0	0	0

 

 

 

 

3. RESULTS AND DISCUSSION:

3.1 ¹H NMR spectra:

 

 

Fig. 2. 1H NMR spectra of the ligand

 

The peaks observed in the ¹H NMR spectra of the Mannich base under study are shown in Fig.2. The signals around 1.0- ppm and 2.5 ppm corresponds to the hydrogens of the piperidine ring. The appearance of peak at 4.3 ppm indicates the methylene hydrogens attached to the nitrogen. The aromatic protons gives a sharp peak at 7.8ppm. Further, the formation of the ligand is ascertained by the disappearance of a signal corresponding to the –NH proton of secondary amine as it was eliminated in the Mannich reaction.

 

 

3.2 IR Spectra:

 

Fig 3. IR Spectra of the ligand

 

 

Fig 4. IR Spectra of the metal complex

 

Table 3 : IR Spectral data of the ligand and the complexes

IR SIGNALS	INTERPRETATION
1718cm-1	>C=O bond
1181cm-1	–C–N-C stretching
1465 cm-1	Angular deformation of C-H

 

The notable signal is the presence of an intense band at ~ 1718 cm^-1 which is due to νC=O carbonyl group. The most observable change in the IR spectra is the disappearance of the – NH stretching vibration and appearance of an intense band at 1181 cm^-1 due to νC-N-C stretching which is formed due to the aminomethylation. The absence of band at 3300 cm^-1 due to amino -NH disappears implying its condensation after deprotonation. These results confirms the formation of the Mannich base.

 

In all the complexes, band due to νC=O and νC-N shifted towards lower frequency viz. 1654 cm^-1 in the case of carbonyl and 1141 cm^-1 for the –CNC clearly indicating the imido nitrogen and carbonyl oxygen are involved in coordination with metal ions. These changes confirms the formation of metal complexes.

 

3.3 UV-Visible spectra:

 

Fig 5. UV Spectra of the ligand and the metal complexes

 

The absorption spectra of the ligand and metal complexes in methanol were recorded over the wavelength range of 200 to 800 nm. The UV spectrum of the Mannich base ligand showed sharp absorption maxima and the three main absorption bands at 203, 240 and 290 nm. The first band due to π→π* transitions of the aromatic rings, underwent blue shift in the complexes indicating the metal complex formation. The second band ca. 240 nm is assigned to the carbonyl group of ligand chromophore. Further weak d→d transitions were observed owing to the transition metals being Laporte forbidden and hence these spectra were recorded at 100 ppm. Based on the foregoing observations f and rom the NMR spectral data and the IR spectral data of both the ligand and the metal complexes, the structure of the so formed complexes can be concluded as given below.

 

 

 

Where M- Cu, Co or Ni

 

3.4 Antimicrobial activity:

The ligand as well as the complexes were screened for antibacterial activity against certain pathogenic bacteria by disc diffusion method at concentration of 10µg / ml in DMSO using Bascillus subtilis, Staphaylococcus aureus, Escherichia coli and Pseudomonas aeruginosaa. The zone of inhibition was measured in mm and the activity was compared with Gentamycin in 1 µg / disc. The results showed that the chelating tends to make the ligand act as more potent bactericidal agents, thus destroying more bacteria than the free ligand. Such increased activity of metal chelates can be explained on the basis of overtone concept and chelation theory. According to the overtone concept of cell permeability, the lipid membrane that surrounds the cell favours the passage of only lipid-soluble materials in which liposolubility is an important factor that controls the anti microbial activity. On chelation it increases the delocalization of π-electrons over the whole chelate ring and enhances the lipophilicity of complexes. This lipophilicity enhances the penetration of complexes into the lipid membranes and blocks the metal binding sites in enzymes of microorganisms. These complexes also disturb the respiration process of the cell and thus block the synthesis of proteins, which restricts further growth of the organism.

 

4. CONCLUSION:

A new Mannich base ligand has been synthesized using Phthalimide and made into complexation with three transition metals. All the four compounds, viz., the ligand and the three complexes, were characterized by physicochemical and spectral methods. It has been observed that the ligand behaves as a bidentate chelating agent thro the N and O donor sites thro the imide and carbonyl moieties respectively. The spectroscopic data is in support of our expected structure. All the three complexes were of octahedral geometry. The antimicrobial property of the the ligand and the complexes were studied and found that complexes possess better antibacterial activity than that of the free ligand and the copper complex is more potent than the other two complexes.

 

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Received on 14.05.2018   Modified on 16.06.2018

Accepted on 27.06.2018   © AJRC All right reserved